Activation of β2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levalbuterol relaxes the smooth muscles of the airways, from the trachea to the terminal bronchioles. Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. The chemical name for levalbuterol HCl is (R)-α1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride.
Levalbuterol HCl has been synthesized using a variety of synthetic schemes. For example, Great Britain patent No. 1298494 discloses synthesizing levalbuterol first by crystallizing the alkyl acetate of the 4-carboxylate derivative (Formula 1) using ditolyltartaric acid and isolating the selected crystalline fraction. Thereafter, the crystal undergoes debenzylation deprotection, followed by ester reduction to yield levalbuterol.

Several patents report synthetic routes using enantiomeric separation, however, the synthetic routes result in low yields of the enantiomerically pure product. Optically pure levalbuterol was synthesized by the borane-methylsulfide reduction of the enantiomerically pure precursor (Formula 2) as described in U.S. Pat. No. 5,399,765. The reaction dissolved a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from (−)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol, upon cooling one stereoisomer crystallized, which was separated, and recrystallized as a diastereomer from methanol, the diastereomer was separated, treated with base, and upon reduction formed optically active levalbuterol.

U.S. Pat. No. 5,442,118 discloses the synthesis of optically pure (R) or (S) levalbuterol by the asymmetric reduction of α-iminoketones precursors. In particular, levalbuterol is synthesized by the reduction with borane-methylsulfide complex in the presence of chiral oxazaborolidines as catalysts.
During the synthesis of levalbuterol, D-dibenzoyltartaric acid (D-DBTA) or D-ditoluoyltartaric acid (D-DTTA) have been used for enantiomeric separation. Typically, during the enantiomeric separation, at least one of the alcohol, ester, or amine functional groups on levalbuterol is protected. The protecting group is typically a benzyl group, which after separation is removed to yield levalbuterol. See U.S. Pat. No. 5,545,745 and WO 95/32178.
The prior art has separated levalbuterol enantiomers using 4-benzyl levalbuterol. See WO 02/48090. The synthesis uses tartaric acid for enantiomeric separation and once the (L) tartaric acid salt is formed and one enantiomer separated, then the salt is debenzylated to yield either the (R) or (S) isomer of salbutamol as a sulphate salt.
Other publications have separated levalbuterol derivatives, such as WO 99/42460, by forming the ketal derivative of levalbuterol prior to enantiomeric separation with an enantiomer of di-O-benzoyl tartaric acid or di-O-(p-toluoyl)-tartaric acid. Thus, after enantiomeric separation of the ketal, the derivative is hydrolyzed to yield the desired levalbuterol enantiomer. The process continuously recycles the undesired enantiomer in the derivatize, resolve, and hydrolyze cycle to further enhance the overall yield of the desired enantiomer.
In Chinese patent No. 1,273,966, enantiomers of racemic salbutamol are separated using tartaric acid, D-DBTA, D-DTTA, or a mixture thereof as a resolving agent. In the examples provided, the ratios of reaction solvent to salbutamol were at least about 14 ml/g. Levalbuterol hydrochloride is isolated by acid-base work-up or by solid-solid transformation in acetone. In one example, the salt of (R)-levalbuterol D-dibenzoyltartaric acid is treated with potassium carbonate in water and an organic solvent, such as ethylacetate. After phase separation and extraction of the aqueous layer, the organic layer is dried and the levalbuterol free base is precipitated overnight. Levalbuterol HCl is synthesized by acid displacement from (R)-levalbuterol D-dibenzoyltartaric acid salt suspended in acetone and the addition of an ether solution of HCl.
Despite the many attempts of the prior art to synthesize enantiomerically pure levalbuterol, novel synthetic processes of levalbuterol are still needed to reduce the steps necessary for synthesis while maximizing synthetic yield without sacrificing compound purity.